tbuckley/cabot-search huggingface dataset:
Polycomb repressor complex 2 suppresses interferon-responsive MHC-II expression in melanoma cells and is associated with anti-PD-1 resistance
Authors: Jamaal L James, Brandie C Taylor, Margaret L Axelrod, Xiaopeng Sun, Lindsey N Guerin, Paula I Gonzalez-Ericsson, Yu Wang, Violeta Sanchez, Catherine C Fahey, Melinda E Sanders, Yaomin Xu, Emily Hodges, Douglas B Johnson, Justin M Balko
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Despite the remarkable success of immunotherapy in treating melanoma, understanding of the underlying mechanisms of resistance remains limited. Emerging evidence suggests that upregulation of tumor-specific major histocompatibility complex-II (tsMHC-II) serves as a predictive marker for the response to anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) therapy in various cancer types. The genetic and epigenetic pathways modulating tsMHC-II expression remain incompletely characterized. Here, we provide evidence that polycomb repressive complex 2 (PRC2)/EZH2 signaling and resulting H3K27 hypermethylation suppresses tsMHC-II. Methods RNA sequencing data from tumor biopsies from patients with cutaneous melanoma treated with or without anti-PD-1, targeted inhibition assays, and assays for transposase-accessible chromatin with sequencing were used to observe the relationship between EZH2 inhibition and interferon (IFN)-γ inducibility within the MHC-II pathway. Results We find that increased EZH2 pathway messenger RNA (mRNA) expression correlates with reduced mRNA expression of both presentation and T-cell genes. Notably, targeted inhibition assays revealed that inhibition of EZH2 influences the expression dynamics and inducibility of the MHC-II pathway following IFN-γ stimulation. Additionally, our analysis of patients with metastatic melanoma revealed a significant inverse association between PRC2-related gene expression and response to anti-PD-1 therapy. Conclusions Collectively, our findings demonstrate that EZH2 inhibition leads to enhanced MHC-II expression potentially resulting from improved chromatin accessibility at CIITA , the master regulator of MHC-II. These insights shed light on the molecular mechanisms involved in tsMHC-II suppression and highlight the potential of targeting EZH2 as a therapeutic strategy to improve immunotherapy efficacy.
Curbing the carbon footprint of health care
Authors: None The Lancet Digital Health
Journal: The Lancet Digital Health (2023)

Technology and innovation is a key theme of the 2023 UN Climate Change Conference, COP28, hoping to catalyse the development and deployment of climate solutions to drive down global temperatures and protect human health. The health-care sector contributes approximately 4·6% to global greenhouse gas (GHG) emissions. Will wider adoption of digital health technologies help mitigate this issue, or exacerbate it?
Endoscopic ultrasound-guided hepaticogastrostomy with bridging as reintervention for stent occlusion in malignant hilar biliary obstruction
Authors: Fumitaka Niiya, Hirotoshi Ishiwatari, Junya Sato, Hiroyuki Matsubayashi, Hiroyuki Ono
Journal: Endoscopy (2023)

Placement of multiple metal stents by endoscopic retrograde cholangiopancreatography for malignant hilar biliary obstruction (MHBO) contributes to longer stent patency [1] [2]. However, endoscopic reintervention is technically difficult when stents are occluded [3]. Endoscopic ultrasonography-guided hepaticogastrostomy (EUS-HGS) is performed for the drainage of the left hepatic bile duct in MHBO. A bridging technique during EUS-HGS can be a promising method for treating isolated right hepatic bile duct obstruction [4] [5]. However, the bridging procedure has yet to be performed as a reintervention for obstructed metal stents in MHBO.
The use of an overtube device to assist in advanced therapeutic procedures in patients with a colostomy
Authors: Hameed Rehman, Stefano Sansone, Adolfo Parra-Blanco
Journal: Endoscopy (2023)

Endoscopic therapeutic procedures in patients with a colostomy can be challenging owing to the altered anatomy of the bowel and access difficulties. We report two cases of successful therapeutic colonoscopies in patients with a colostomy using DiLumen (Lumendi, Westport, Connecticut, United States) ([Fig. 1]), which is a new double-balloon device designed to stabilize the endoscopic position and enhance access to the lesion site [1].
Basics of Point-of-Care Lung Ultrasonography
Authors: Natalia Buda, Konrad Mendrala, Szymon Skoczyński, Mathieu Pasquier, Piotr Mazur, Elena Garcia, Tomasz Darocha
Journal: New England Journal of Medicine (2023)

Lung ultrasonography facilitates quick diagnosis at the bedside and is especially useful in emergency conditions. This video describes practical considerations for patients with the most common causes of dyspnea.
High-Resolution and Noninvasive Fetal Exome Screening
Authors: Harrison Brand, Christopher W Whelan, Michael Duyzend, John Lemanski, Monica Salani, Stephanie P Hao, Isaac Wong, Elise Valkanas, Caroline Cusick, Casie Genetti, Lori Dobson, Courtney Studwell, Kathleen Gianforcaro, Louise Wilkins-Haug, Stephanie Guseh, Benjamin Currall, Kathryn Gray, Michael E Talkowski
Journal: New England Journal of Medicine (2023)
Case 36-2023: A 19-Year-Old Man with Diabetes and Kidney Cysts
Authors: Asaf Vivante, Weizhen Tan, Samantha G. Harrington, Miriam S. Udler, Toni I. Pollin
Journal: New England Journal of Medicine (2023)

A 19-year-old man was evaluated because of kidney cysts. Three years earlier, he had received a diagnosis of diabetes when abdominal pain and increased urinary frequency had developed. A diagnosis was made.
Predicting seizure recurrence after an initial seizure-like episode from routine clinical notes using large language models: a retrospective cohort study
Authors: Brett K Beaulieu-Jones, Mauricio F Villamar, Phil Scordis, Ana Paula Bartmann, Waqar Ali, Benjamin D Wissel, Emily Alsentzer, Johann de Jong, Arijit Patra, Isaac Kohane
Journal: The Lancet Digital Health (2023)

The evaluation and management of first-time seizure-like events in children can be difficult because these episodes are not always directly observed and might be epileptic seizures or other conditions (seizure mimics). We aimed to evaluate whether machine learning models using real-world data could predict seizure recurrence after an initial seizure-like event. This retrospective cohort study compared models trained and evaluated on two separate datasets between Jan 1, 2010, and Jan 1, 2020: electronic medical records (EMRs) at Boston Children's Hospital and de-identified, patient-level, administrative claims data from the IBM MarketScan research database. The study population comprised patients with an initial diagnosis of either epilepsy or convulsions before the age of 21 years, based on International Classification of Diseases, Clinical Modification (ICD-CM) codes. We compared machine learning-based predictive modelling using structured data (logistic regression and XGBoost) with emerging techniques in natural language processing by use of large language models. The primary cohort comprised 14 021 patients at Boston Children's Hospital matching inclusion criteria with an initial seizure-like event and the comparison cohort comprised 15 062 patients within the IBM MarketScan research database. Seizure recurrence based on a composite expert-derived definition occurred in 57% of patients at Boston Children's Hospital and 63% of patients within IBM MarketScan. Large language models with additional domain-specific and location-specific pre-training on patients excluded from the study (F1-score 0·826 [95% CI 0·817-0·835], AUC 0·897 [95% CI 0·875-0·913]) performed best. All large language models, including the base model without additional pre-training (F1-score 0·739 [95% CI 0·738-0·741], AUROC 0·846 [95% CI 0·826-0·861]) outperformed models trained with structured data. With structured data only, XGBoost outperformed logistic regression and XGBoost models trained with the Boston Children's Hospital EMR (logistic regression: F1-score 0·650 [95% CI 0·643-0·657], AUC 0·694 [95% CI 0·685-0·705], XGBoost: F1-score 0·679 [0·676-0·683], AUC 0·725 [0·717-0·734]) performed similarly to models trained on the IBM MarketScan database (logistic regression: F1-score 0·596 [0·590-0·601], AUC 0·670 [0·664-0·675], XGBoost: F1-score 0·678 [0·668-0·687], AUC 0·710 [0·703-0·714]). Physician's clinical notes about an initial seizure-like event include substantial signals for prediction of seizure recurrence, and additional domain-specific and location-specific pre-training can significantly improve the performance of clinical large language models, even for specialised cohorts. UCB, National Institute of Neurological Disorders and Stroke (US National Institutes of Health).
Comprehensive Noninvasive Fetal Screening by Deep Trio-Exome Sequencing
Authors: Ieva Miceikaitė, Qin Hao, Charlotte Brasch-Andersen, Christina R Fagerberg, Pernille M Torring, Britta S Kristiansen, Lilian B Ousager, Lene Sperling, Mette H Ibsen, Katrin Löser, Martin J Larsen
Journal: New England Journal of Medicine (2023)
The association of a disability-targeted cash transfer programme with disability status and health-care access: a quasi-experimental study using a nationwide cohort of 4·3 million Chinese adults living with severe disabilities
Authors: Zhihui Li, Hongchuan Wang, Shaoru Chen, Yuhao Kong, Lifeng Xie, Xiangda Zhang, Chunling Lu, S V Subramanian, Jessica L Cohen, Rifat Atun
Journal: The Lancet Public Health (2023)

Cash transfer is a crucial policy tool to address inequality. The objective of this study was to investigate the association between China's disability-targeted cash transfer programme and disability status, as well as equitable access to rehabilitation and medical services.For this quasi-experimental study, we drew data from the nationwide administrative cohort of individuals with disabilities between Jan 1, 2015, and Dec 31, 2019. Individuals were enrolled in the cohort if they were aged 18 years or older, had severe disabilities as defined by the Chinese Government, and had available cash transfer information for at least 4 consecutive years, without having started receiving cash transfer benefits at the time of enrolment. We used a quasi-experimental design with propensity score matching to estimate the effects of cash transfers on disability status, access to rehabilitation services, and access to medical treatment. The primary outcomes were development of new disability and reduction of existing disabilities. Secondary outcomes were use of rehabilitation services, financial barriers as a major obstacle to accessing rehabilitation services, use of medical services by individuals who had an illness in the previous 2 weeks, and financial barriers as a major obstacle to accessing medical services.From an initial pool of 51 356 125 individuals with disabilities registered in the administrative system, 2 686 024 individuals were eligible for analysis, of whom 2 165 335 (80·6%) were cash transfer beneficiaries and 520 689 (19·4%) non-beneficiaries. After propensity score matching, the cohort included 4 330 122 adults with severe disabilities. Cash transfer beneficiaries had significantly lower odds of developing new disabilities over time than non-beneficiaries (odds ratio [OR] 0·90, 95% CI 0·86-0·94; p<0·0001) and higher odds of having a reduced number of disabilities over time (1·17, 1·10-1·25; p<0·0001). Compared with non-beneficiaries, cash transfer beneficiaries were more likely to use rehabilitation services (2·12, 2·11-2·13; p<0·0001) and medical services (1·74, 1·69-1·78; p<0·0001), and less likely to report financial hardship to access rehabilitation services (0·53, 0·52-0·54; p<0·0001) and medical services (0·88, 0·84-0·93; p<0·0001) at the study endpoint.The receipt of cash transfers was associated with improved disability status and increased access to disability-related services. The findings suggest that cash transfers could be a potential method for promoting universal health coverage among individuals living with disabilities.China National Natural Science Foundation.
Why are so many enteric pathogen infections asymptomatic? Pathogen and gut microbiome characteristics associated with diarrhea symptoms and carriage of diarrheagenic <i>E. coli</i> in northern Ecuador
Authors: Kelsey J Jesser, Gabriel Trueba, Konstantinos T. Konstantinidis, Karen Levy
Journal: Gut Microbes (2023)

A high proportion of enteric infections, including those caused by diarrheagenic Escherichia coli (DEC), are asymptomatic for diarrhea. The factors responsible for the development of diarrhea symptoms, or lack thereof, remain unclear. Here, we used DEC isolate genome and whole stool microbiome data from a case–control study of diarrhea in Ecuador to examine factors associated with diarrhea symptoms accompanying DEC carriage. We investigated i) pathogen abundance, ii) gut microbiome characteristics, and iii) strain-level pathogen characteristics from DEC infections with diarrhea symptoms (symptomatic infections) and without diarrhea symptoms (asymptomatic infections). We also included data from individuals with and without diarrhea who were not infected with DEC (uninfected cases and controls). i) E. coli relative abundance in the gut microbiome was highly variable, but higher on-average in individuals with symptomatic compared to asymptomatic DEC infections. Similarly, the number and relative abundances of virulence genes in the gut were higher in symptomatic than asymptomatic DEC infections. ii) Measures of microbiome diversity were similar regardless of diarrhea symptoms or DEC carriage. Proteobacterial families that have been described as pathobionts were enriched in symptomatic infections and uninfected cases, whereas potentially beneficial taxa, including the Bacteroidaceae and Bifidobacteriaceae, were more abundant in individuals without diarrhea. An analysis of high-level gene functions recovered in metagenomes revealed that genes that were differentially abundant by diarrhea and DEC infection status were more abundant in symptomatic than asymptomatic DEC infections. iii) DEC isolates from symptomatic versus asymptomatic individuals showed no significant differences in virulence or accessory gene content, and there was no phylogenetic signal associated with diarrhea symptoms. Together, these data suggest signals that distinguish symptomatic from asymptomatic DEC infections. In particular, the abundance of E. coli, the virulence gene content of the gut microbiome, and the taxa present in the gut microbiome have an apparent role.
The Changing Landscape of Aortic-Valve Stenosis Management
Authors: Ulf Landmesser
Journal: New England Journal of Medicine (2023)

Aortic-valve stenosis is an increasingly important cause of cardiovascular disease, particularly among older adults, with an overall prevalence of 2.8% among adults older than 75 years of age.1 Aortic stenosis is a progressive disease in which the rate of change of the aortic-valve area is estimated to be 0.1 cm2 annually, although there is wide variability among patients. In the absence of therapies to prevent or slow progression toward severe aortic stenosis, which remains a major unmet clinical need,2 timely aortic-valve replacement represents the main treatment option. As early as 1990, Dr. Eugene Braunwald opined that the most important decision . . .
Oral VV116 versus placebo in patients with mild-to-moderate COVID-19 in China: a multicentre, double-blind, phase 3, randomised controlled study
Authors: Xiaohong Fan, Xiahong Dai, Yun Ling, Lihua Wu, Lingling Tang, Chunxian Peng, Chaolin Huang, Hongyan Liu, Hongzhou Lu, Xinghua Shen, Wei Zhang, Furong Wang, Guangming Li, Ming Li, Yanming Huang, Hongying Zhang, Minghui Li, Fei Ren, Yuanyuan Li, Chenfan Liu, Zhiguo Zhou, Wei Sun, Yongxiang Yi, Daming Zhou, Hainv Gao, Qi Pan, Hongde Liu, Jiang Zhao, Zhen Ding, Yingmin Ma, Wei Li, Quanhong Wang, Xicheng Wang, Yichun Bai, Xiangao Jiang, Juan Ma, Bingying Xie, Kui Zhang, Lanjuan Li
Journal: The Lancet Infectious Diseases (2023)
Platinum-Based Chemotherapy Attenuates the Effector Response of CD8 T Cells to Concomitant PD-1 Blockade
Authors: Annapaola Mariniello, Tahseen H. Nasti, Daniel Y. Chang, Masao Hashimoto, Sakshi Malik, Daniel T. McManus, Judong Lee, Donald J. McGuire, Maria A. Cardenas, Pablo Umana, Valeria Nicolini, Rustom Antia, Ananya Saha, Zachary Buchwald, Hayden Kissick, Ehsan Ghorani, Silvia Novello, Dario Sangiolo, Giorgio V. Scagliotti, Suresh S. Ramalingam, Rafi Ahmed
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Combination of chemotherapy with programmed cell death 1 (PD-1) blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how chemotherapy affects the response of exhausted CD8 T cells to PD-1 blockade. Experimental Design: We used the well-established mouse model of T-cell exhaustion with chronic lymphocytic choriomeningitis virus (LCMV) infection to assess the effect of chemotherapy (cisplatin+pemetrexed) on T-cell response to PD-1 blockade, in the absence of the impact of chemotherapy on antigen release and presentation observed in tumor models. Results: When concomitantly administered with PD-1 blockade, chemotherapy affected the differentiation path of LCMV-specific CD8 T cells from stem-like to transitory effector cells, thereby reducing their expansion and production of IFNγ. After combination treatment, these restrained effector responses resulted in impaired viral control, compared with PD-1 blockade alone. The sequential combination strategy, where PD-1 blockade followed chemotherapy, proved to be superior to the concomitant combination, preserving the proliferative response of exhausted CD8 T cells to PD-1 blockade. Our findings suggest that the stem-like CD8 T cells themselves are relatively unaffected by chemotherapy partly because they are quiescent and maintained by slow self-renewal at the steady state. However, upon the proliferative burst mediated by PD-1 blockade, the accelerated differentiation and self-renewal of stem-like cells may be curbed by concomitant chemotherapy, ultimately resulting in impaired overall CD8 T-cell effector functions. Conclusions: In a translational context, we provide a proof-of-concept to consider optimizing the timing of chemo-immunotherapy strategies for improved CD8 T-cell functions. See related commentary by Vignali and Luke, p. 1705
Liver Transplantation for Mahvash Disease, an Inborn Error of Metabolism
Authors: Pramod K. Mistry, Guadalupe Garcia-Tsao
Journal: New England Journal of Medicine (2023)

The treatment by liver transplantation of a patient with Mahvash disease, which is characterized by pancreatic neuroendocrine tumors, extends understanding of the biochemical processes undergirding its signs and symptoms.
Liver Transplantation in a Woman with Mahvash Disease
Authors: Justin Robbins, Dina Halegoua-DeMarzio, Atrayee Basu Mallick, Namrata Vijayvergia, Rebecca Ganetzky, Harish Lavu, Veda N. Giri, Jeffrey Miller, Warren Maley, Ashesh P. Shah, Matthew DiMeglio, Manju Ambelil, Run Yu, Takami Sato, Daniel S. Lefler
Journal: New England Journal of Medicine (2023)

Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.
Temporal Variation in Introgressed Segments’ Length Statistics Computed from a Limited Number of Ancient Genomes Sheds Light on Past Admixture Pulses
Authors: Lionel N Di Santo, Claudio S Quilodrán, Mathias Currat
Journal: Molecular Biology and Evolution (2023)

Abstract Hybridization is recognized as an important evolutionary force, but identifying and timing admixture events between divergent lineages remain a major aim of evolutionary biology. While this has traditionally been done using inferential tools on contemporary genomes, the latest advances in paleogenomics have provided a growing wealth of temporally distributed genomic data. Here, we used individual-based simulations to generate chromosome-level genomic data for a 2-population system and described temporal neutral introgression patterns under a single- and 2-pulse admixture model. We computed 6 summary statistics aiming to inform the timing and number of admixture pulses between interbreeding entities: lengths of introgressed sequences and their variance within genomes, as well as genome-wide introgression proportions and related measures. The first 2 statistics could confidently be used to infer interlineage hybridization history, peaking at the beginning and shortly after an admixture pulse. Temporal variation in introgression proportions and related statistics provided more limited insights, particularly when considering their application to ancient genomes still scant in number. Lastly, we computed these statistics on Homo sapiens paleogenomes and successfully inferred the hybridization pulse from Neanderthal that occurred approximately 40 to 60 kya. The scarce number of genomes dating from this period prevented more precise inferences, but the accumulation of paleogenomic data opens promising perspectives as our approach only requires a limited number of ancient genomes.
DegronMD: Leveraging Evolutionary and Structural Features for Deciphering Protein-Targeted Degradation, Mutations, and Drug Response to Degrons
Authors: Haodong Xu, Ruifeng Hu, Zhongming Zhao
Journal: Molecular Biology and Evolution (2023)

Protein-targeted degradation is an emerging and promising therapeutic approach. The specificity of degradation and the maintenance of cellular homeostasis are determined by the interactions between E3 ubiquitin ligase and degradation signals, known as degrons. The human genome encodes over 600 E3 ligases; however, only a small number of targeted degron instances have been identified so far. In this study, we introduced DegronMD, an open knowledgebase designed for the investigation of degrons, their associated dysfunctional events, and drug responses. We revealed that degrons are evolutionarily conserved and tend to occur near the sites of protein translational modifications, particularly in the regions of disordered structure and higher solvent accessibility. Through pattern recognition and machine learning techniques, we constructed the degrome landscape across the human proteome, yielding over 18,000 new degrons for targeted protein degradation. Furthermore, dysfunction of degrons disrupts the degradation process and leads to the abnormal accumulation of proteins; this process is associated with various types of human cancers. Based on the estimated phenotypic changes induced by somatic mutations, we systematically quantified and assessed the impact of mutations on degron function in pan-cancers; these results helped to build a global mutational map on human degrome, including 89,318 actionable mutations that may induce the dysfunction of degrons and disrupt protein degradation pathways. Multiomics integrative analysis unveiled over 400 drug resistance events associated with the mutations in functional degrons. DegronMD, accessible at https://bioinfo.uth.edu/degronmd, is a useful resource to explore the biological mechanisms, infer protein degradation, and assist with drug discovery and design on degrons.